Technical Field
The invention relates to (indazol-4-yl)hexahydropyrrolopyrrolones that are sodium channel (e.g., Nav1.7 and Nav1.8) blockers, useful in treating diseases and conditions mediated and modulated by the voltage-gated sodium channels. Additionally, the invention relates to compositions containing compounds of the invention and processes of their preparation.
Description of Related Technology
The voltage-gated sodium channels (VGSCs, Nav1.x) contribute to the initiation and propagation of action potentials in excitable tissues such as nerve and muscle by modulating the influx of sodium ions. Nav1.7, one of nine sodium channel isoforms, is preferentially expressed in the peripheral nervous system where it acts as a threshold channel for action potential firing in neurons (Cummins T R, et al. Expert Rev Neurother 2007; 7:1597-1612. Rush A M, et al. J Physiol 2007; 579:1-14.). A wealth of evidence connects abnormal activity of sodium channels in the peripheral nervous system to the pathophysiology of chronic pain (Goldin A L, et al. Neuron 2000; 28:365-368. Dib-Hajj S D, et al. Annu Rev Neurosci 2010; 33:325-347.). Polymorphisms in SCN9A, the gene that encodes Nav1.7, cause human pain disorders arising from either gain-of-function or loss-of-function mutations of the channel. Clinically, VGSC blockers have proven useful in the management of pain, but their utility is often limited by incomplete efficacy and poor tolerability. Local anesthetics (e.g., lidocaine), anti-arrhythmic agents (e.g., mexilitene), and anti-convulsants (e.g., lamotrigine) are all relatively weak (IC50 values in the high micromolar range), non-selective (versus Nav1.x subtypes and other ion channels) VGSC blocking agents identified without prior knowledge of their molecular targets.
The VGSCs are integral plasma membrane proteins composed of a large (260 kDa) α-subunit and one or more smaller β-subunits (Hargus N J et al. Expert Opin Invest Drugs 2007; 16:635-646). Nine α-subunits (Nav1.1-Nav1.9) and four β-subunits (β1-β4) have been identified in mammals. The various VGSC subtypes exhibit diverse functional properties and distinct expression patterns, suggesting differential involvement in transmission of specific signals. Nav1.7, Nav1.8 and Nav1.9 are expressed predominantly in the peripheral nervous system in humans and rodents (Waxman S G Brain 2010; 133:2515-2518). The biophysical characteristics of Nav1.7 suggest a role in initiation of action potentials, while Nav1.8 is a major contributor to the upstroke of action potentials in sensory neurons. Nav1.9 produces a persistent current that is involved in setting the resting membrane potential.
The Nav1.7 isoform is expressed in both small and large diameter dorsal root ganglion (DRG) neurons, as well as in sympathetic neurons, and in peripheral axonal termini of neurons processing pain. Nav1.7 is up-regulated in preclinical models of inflammatory and neuropathic pain, including diabetic neuropathy (Dib-Hajj S D, et al. Nat Rev Neurosci. 2013; 14:49-62. Hong S, et al. Journal of Biological Chemistry. 2004; 279:29341-29350. Persson A K, et al. Exp Neurol. 2011; 230:273-279.). Nav1.7 has been shown to accumulate in painful neuromas, such as those in amputees with phantom limb pain, and in painful dental pulp (Beneng K, et al. BMC Neurosci. 2010; 11:71. Dib-Hajj S D, et al. Nat Rev Neurosci. 2013; 14:49-62). Rare human genetic conditions involving single-nucleotide polymorphisms in SCN9A, the gene encoding for Nav1.7 highlight its importance in pain pathways. Bi-allelic gain-of-function mutations (enhancing channel activity and increasing the excitability of DRG neurons) produce severe pain syndromes with dominant genetic inheritance. Mutations that hyperpolarize activation voltage dependence (i.e., facilitate channel opening and increase the excitability of DRG neurons) result in inherited erythromelalgia (IEM), a condition characterized by excruciating burning pain, attacks of edema, increased skin temperature and flushing of the skin affecting the distal extremities. Similarly, polymorphisms that impair inactivation of the channel and enhance persistent current lead to paroxysmal extreme pain disorder (PEPD), a condition wherein episodic severe perineal, perioccular and paramandibular pain is accompanied by autonomic manifestations such as skin flushing usually in the lower body (Waxman S G Nature 2011472:173-174. Dib-Hajj S D, et al. Brain 2005; 128:1847-1854.). By contrast, bi-allelic loss-of-function mutations preventing the production of functional Nav1.7 channels produced channelopathy-associated congenital insensitivity to pain (CIP). CIP patients do not perceive or understand pain even when confronted with extreme pain stimuli such as bone fractures, surgery, dental extractions, burns, and childbirth.
The role of Nav1.7 in pain has been confirmed in knockout studies. Global deletion of Nav1.7 in knockout mice causes a disruption of normal eating behavior due to a deficit in olfaction, resulting in lethality shortly after birth (Nassar M A, et al. Proc Natl Acad Sci USA 2004; 101:12706-12711). A conditional Nav1.7 knockout in Nav1.8-expressing DRG neurons abrogated inflammation-induced pain and diminished responses to mechanical insult, but neuropathic pain development was not affected (Nassar M A, et al. Mol Pain 2005; 1:24-31). However, ablation of Nav1.7 in both sensory and sympathetic neurons recapitulated the pain-free phenotype seen in CIP patients, abolishing inflammatory and neuropathic pain without causing any overt autonomic dysfunction (Minett M S, et al. Nat Commun 2012; 3:791). Nav1.7-deficient sensory neurons also failed to release substance P in the spinal cord or to display synaptic potentiation in the dorsal horn of the spinal cord in response to electrical stimulation of the sciatic nerve (Minett M S, et al. Nat Commun 2012; 3:791).
The level of preclinical validation for the Nav1.8 isoform as a target for pain is also compelling. Complementary to Nav1.7 in its biophysical and functional profile, the Nav1.8 isoform is expressed in nociceptive trigeminal neurons, in the vast majority of DRG neurons, and in peripheral free nerve endings (Shields S D, et al. Pain 2012; 32:10819-10832). An evaluation of Nav1.8-null mice demonstrated that this channel carries the majority of current underlying the upstroke of the action potential in nociceptive neurons. Knockout studies further implicate Nav1.8 in visceral, cold, and inflammatory pain, but not in neuropathic pain. However, assessment of Nav1.8 antisense oligonucleotides, also suggested involvement of Nav1.8 in the development and maintenance of neuropathic pain, in addition to confirming the relevance of the channel in inflammatory pain (Momin A, et al. Curr Opin Neurobiol 2008; 18:383-388. Rush A M, et al. J Physiol 2007; 579:1-14. Liu M et al. Pain Med 12 Suppl 2011; 3:593-99.). Human gain-of-function mutations in Nav1.8 were recently identified in patients with small fiber neuropathy (SFN) who were all negative for mutations in Nav1.7 (Faber C G, et al. Proc Natl Acad Sci USA. 2012; 109:19444-19449).
While the literature offers preclinical validation for Nav1.7 and Nav1.8 as pain targets, multiple challenges confront the discovery and development of small molecule blockers. The potency needed for efficacy, the levels of selectivity versus the various isoforms required for acceptable therapeutic index, and the relevance of state- and use-dependent activity are not well understood. For example, with respect to selectivity, the human ether-a-go-go-related gene (hERG, Kv11.1) is a potassium channel responsible for the rapidly activating repolarization current IKr that has a critical role in cardiac electrophysiology and drug safety. hERG inhibition is the most common mechanism of drug-induced QT prolongation and torsades de pointes (TdP) arrhythmia. The study of hERG has become an important predictor of cardiac risk (Rampe, D, et al. Journal of Pharmacological and Toxicological Methods 2013; 68:13-22), and it is desirable to have selectivity for voltage-gated sodium channels over hERG.
Although compounds and mechanisms exist that are used clinically to treat pain, there is need for new compounds that can effectively treat different types of pain. Pain of various types (e.g., inflammatory pain, post-surgical pain, osteoarthritis pain, knee pain, lower back pain, neuropathic pain) afflicts virtually all humans and animals at one time or another, and a substantial number of medical disorders and conditions produce some sort of pain as a prominent concern requiring treatment. As such, it would be particularly beneficial to identify new compounds for treating the various types of pain.